Combining "Disease in a Dish" and "Drug Discovery in a Dish" to Improve Patient Care

by Amanda Chase, PhD
September 9, 2021

Almost one million individuals are hospitalized every year in the United States for cardiac arrhythmias, or an irregular heartbeat. This makes cardiac arrhythmias a leading cause of healthcare expenditures, with a direct cost close to $50 billion annually for diagnosis, treatment, and rehabilitation. Ventricular cardiac arrhythmia (VA) is when the abnormal heartbeat starts in the ventricles, or lower heart chambers. As the heart beats too fast, it prevents oxygen-rich blood from circulating to the brain and body, which may result in cardiac arrest. In fact, about 300,000 individuals die of sudden arrhythmic death syndrome each year.

Although arrhythmias are very common in older adults, treatment options include drugs that have significant side effects, and there is a need for improved treatment options. In a recent Journal of Medicinal Chemistry publication, stem cell biologists from the Cardiovascular Institute, medicinal chemists from the Human BioMolecular Research Institute (HBRI), and cardiovascular pharmacologists from UCLA worked together to address this need by creating an alternative version of a drug that had decreased severe side effects. The team was led by Mark Mercola at the Cardiovascular Institute and Department of Medicine at Stanford University and John Cashman at the HBRI.

Induced pluripotent stem cells (iPSCs) have provided a new way to model and learn about diseases: disease in a dish. The disease-in-a-dish concept also allows researchers to test new drugs to better determine how effective they are and if they are safe. In this publication, the team used iPSC cells from patients with long QT syndrome (LQTS), a type of VA that can occur from birth, to design improved drugs similar to mexiletine. Mexiletine is a drug used to treat life-threatening VAs that has been seen to lead to worsened arrythmias. The re-engineered analogues were evaluated in healthy iPSC-derived cardiomyocytes (iPSC-CMs) to evaluate their safety. At the same time, they were evaluated in iPSC-CMs from patients with LQTS to determine how effective they were at improving the arrhythmias.  

This is the first report of using iPSC-CMs from both normal and diseased individuals to re-engineer a drug and evaluating its safety and effectiveness, combining “drug development in a dish” and “disease in a dish” to develop a compound of use in treating cardiovascular disease. Aside from generating a potentially improved therapy for VA, this publication also shows that drug development can effectively be done using “drug discovery in a dish” and “disease in a dish” to develop new and safer drugs.

Stanford Cardiovascular Institute affiliated author also includes Wesley McKeithan. Authors were joined by medicinal chemists at the Human BioMolecular Research Institute, Columbia University, and University of California, Los Angeles.